Deoxypodophyllotoxin Inhibits Cell Growth and Induces Apoptosis by Blocking EGFR and MET in Gefitinib-Resistant Non-Small Cell Lung Cancer
Han Sol Kim, Ha‐Na Oh, Ah‐Won Kwak, Eunae Kim, Mee‐Hyun Lee, Ji‐Hye Seo, Seung‐Sik Cho, Goo Yoon, Jung‐Il Chae, Jung‐Hyun Shim
Abstract
roots exhibits various pharmacological activities including anti-inflammation and anti-cancer effects. In this study we sought to determine the anti-cancer effects of DPT on HCC827GR cells, which are resistant to gefitinib (EGFR-TKI) due to regulation of EGFR and MET and their related signaling pathways. To identify the direct binding of DPT to EGFR and MET, we performed pull-down, ATP-binding, and kinase assays. DPT exhibited competitive binding with ATP against the network kinases EGFR and MET and reduced their activities. Also, DPT suppressed the expression of p-EGFR and p-MET as well as their downstreat proteins p-ErbB3, p-AKT, and p-ERK. The treatment of HCC827GR cells with DPT induced high ROS generation that led to endoplasmic-reticulum stress. Accordingly, loss of mitochondrial membrane potential and apoptosis by multi-caspase activation were observed. In conclusion, these results demonstrate the apoptotic effects of DPT on HCC827GR cells and signify the potential of DPT to serve as an adjuvant anti-cancer drug by simultaneously inhibiting EGFR and MET.